Table of contents
Table of contents
................................................................................................................... 2
1. Introduction....................................................................................................................... 3
1.3. Search and assessment methodology....................................................................
7
2. Historical data on medicinal use ........................................................................................ 7
2.1. Information on period of medicinal use in the Community ........................................
7
preparations and indications..................................................................................... 1
0
3. Non-Clinical Data ............................................................................................................. 12
preparation(s) and relevant constituents thereof ......................................................... 1
2
3.1.1. Overall conclusion on pharmacology: ............................................................... 1
3
preparation(s) and relevant constituents thereof ......................................................... 1
3
preparation(s) and constituents thereof ..................................................................... 1
3
3.3.1. Overall conclusion on toxicological data ............................................................ 1
3
3.4. Overall conclusions on non-clinical data............................................................... 1
4
4. Clinical Data ..................................................................................................................... 14
4.1. Clinical Pharmacology ....................................................................................... 1
4
including data on relevant constituents ...................................................................... 1
4
including data on relevant constituents ...................................................................... 1
4
4.2. Clinical Efficacy ................................................................................................ 1
4
4.2.1. Dose response studies.................................................................................... 1
4
4.2.2. Clinical studies (case studies and clinical trials).................................................. 1
4
4.2.3. Clinical studies in special populations (e.g. elderly and children)........................... 1
5
4.3. Overall conclusions on clinical pharmacology and efficacy ...................................... 1
5
5. Clinical Safety/Pharmacovigilance................................................................................... 15
5.1. Overview of toxicological/safety data from clinical trials in humans.......................... 1
5
5.2. Patient exposure .............................................................................................. 1
5
5.3. Adverse events and serious adverse events and deaths ......................................... 1
5
5.4. Laboratory findings .......................................................................................... 1
5
5.5. Safety in special populations and situations ......................................................... 1
5
5.6. Overall conclusions on clinical safety ................................................................... 1
6
Assessment report on
Filipendula ulmaria
(L.) Maxim. (=
Spiraea ulmaria
(L.)), herba
and
Filipendula ulmaria
(L.) Maxim. (=
Spiraea ulmaria
(L.)), flos
EMA/HMPC/434892/2010
Page 2/17
1.
Introduction
1.1.
Description of the herbal substance(s), herbal preparation(s) or
combinations thereof
Herbal substance(s)
Filipendulae ulmariae herba consists of the whole or cut, dried flowering tops of
Filipendula ulmaria
(L.)
Maxim. (syn.:
Spiraeae ulmaria
(L.)). The material complies with the Ph. Eur. monograph (ref.:
01/2008:1868)
For Filipendulae ulmariae flos no Ph. Eur. monograph is available. Descriptions are derived from Wichtl
(1994) and the Complete German Commission E. (Blumenthal, 1998). Wichtl defines Spiraeae flos as
the dried flowers of
Filipendula ulmaria
(L.) Maxim. and provides extensive macroscopic and
microscopic descriptions. According to the Commission E monograph Spiraeae flos consists of the dried
flower of
Filipendula ulmaria
(L.) Maxim. (syn.:
Spiraeae ulmaria
(L.)) as well as its preparations in
effective dosage (Blumenthal, 1998).
In the European countries
Filipendula ulmaria
is designated as follows: English: Meadowsweet,
Bittersweet, Bridewort, Goat’s beard, Honey-sweet, Queen of the meadows, Sweet hay; French: Reine
des prés, Barbe de bouc, Barbe de chèvre, Belle des prés, Ulmaire; German: Echtes Mädesüβ,
Bocksbart, Geiβbart, Spierstaude, Sumpfkraut, Wiesenkönigin; Dutch: Moerasspiraea, Bloeiende olm,
Geitenbaard, Kamerkruid, Koningin der weide, Olmkruid, Torkruid (Halkes, 1998).
Constituents
: (Wichtl, 1994; Zeylstra, 1998; ESCOP, 2003; Barnes et al., 2007):
The European Pharmacopoeia requires minimum 1 ml/kg of steam-volatile substances for Filipendulae
ulmariae herba.
Salicylates
are the main components of the
volatile oil
, mainly salicylaldehyde (up to
70%). According to ESCOP monograph “Steam distillation of the dried flowers yields a small amount
(0.2%) of volatile oil arising from the phenolic glycosides during drying and storage”.
The amount of salicylates, mostly present in the form of glycosides, is assumed to be less than 0.5%
(Zeylstra, 1998; ESCOP, 2003).
Flavonoids
, from 3-4% in the flowering herb up to 6% in the fresh flowers, in particular spiraeoside
(quercetin-4’-glucoside), also hyperoside, other quercetin and kaempferol derivatives, as kaempferol-
4’-glucoside.
Tannins
(hydrolysable type, ranging from 1% in ethanolic extracts to 12% in aqueous extracts),
predominantly the dimeric compound rugosin D.
Miscellaneous:
coumarin (trace), mucilage, carbohydrates, ascorbic acid.
Herbal preparation(s)
Herb:
A1) Comminuted herbal substance for tea preparation
A2) Powdered herbal substance
B1) Dry extract (DER not available), water
B2) Dry extract (DER not available), water (may be identical to B1)
B3) Liquid extract (1:1; ethanol 25% v/v)
C) Tincture (1:5; ethanol 45% v/v)
Assessment report on
Filipendula ulmaria
(L.) Maxim. (=
Spiraea ulmaria
(L.)), herba
and
Filipendula ulmaria
(L.) Maxim. (=
Spiraea ulmaria
(L.)), flos
EMA/HMPC/434892/2010
Page 3/17
Flowers:
A1) Comminuted herbal substance for tea preparation
B) Dry extract (DER not available), ethanol ? % (v/v)
Combinations of herbal substance(s) and/or herbal preparation(s) including a description of
vitamin(s) and/or mineral(s) as ingredients of traditional combination herbal medicinal products
assessed, where applicable.
According to the British Herbal Pharmacopoeia (1983) Filipendulae ulmariae herba is used in
combinations with
Althaea
and
Melissa
(for gastric conditions), and with
Ballota
(anti-emetic). At
present combination products containing Filipendulae ulmariae herba are on the market in several EU
Member States, amongst others: Czech Republic (combinations with Salicis cortex, Violae tricoloris
herba, Harpagophyti radix, Equiseti herba, Solidaginis herba, Callunae herba, herbal tea for oral use;
indications 1) as an adjuvant for inflammatory and degenerative diseases of locomotors apparatus
(rheumatism, arthrosis, arthritis and gout), 2) adjuvant therapy in flu like symptoms, France (about 10
combination products as herbal teas; indications 1) Traditionally used to promote urinary and digestive
elimination functions, 2) Traditionally used as analgesic (headache, toothache), 3) Traditionally used in
the symptomatic treatment of minor painful joint conditions, and Spain (in combination products as
herbal teas).
Filipendulae ulmariae flos is an ingredient of 6 herbal teas in Germany, each one consisting of
Filipendulae ulmariae flos, Tiliae flos and Sambuci flos. According to Wichtl (1994) the flowers are a
component of some mixed herbal teas as remedies for influenza, rheumatism and kidney-bladder teas.
In the UK some multi-ingredient products containing the flowers or extracts are on the market.
Vitamin(s): not applicable
Mineral(s)
:not applicable
1.2.
Information about products on the market in the Member States
According to the information provided by the National Competent Authorities
Table 1. Specified products on the market in the European Member State
Member
State
Medicinal Product
Regulatory Status
Austria
no medicinal product on the market containing
Filipendula
alone or in combination
Bulgaria
no products with MA
Czech
Republic
no product containing
Filipendula
as a single herbal substance/ herbal preparation is
authorised/registered. Herb: only available in combination products as food
supplements, e.g. a herbal tea, on the market since 1999.
Danmark
no products with MA
Estonia
no medicinal product on the market
France
Herb:
Assessment report on
Filipendula ulmaria
(L.) Maxim. (=
Spiraea ulmaria
(L.)), herba
and
Filipendula ulmaria
(L.) Maxim. (=
Spiraea ulmaria
(L.)), flos
EMA/HMPC/434892/2010
Page 4/17
Arkogélules Reine des Près, powdered herbal substance of dry
flowering tops, hard capsules 300 mg
MA 1988
Dry extract (DER?), water, hard capsule 200 mg
MA
Comminuted herbal substance, sachet 1.5 g
MA
Dry extract (DER?), water, hard capsule 169 mg
MA
Also available in combination products (herbal teas)
- (?)
Flowers:
Dry extract (DER?), ethanol ? % (v/v), hard capsule 50 mg
-
Germany
Herb: no products on the market
Flowers: single active ingredient: 3 herbal teas
combination products: 6 herbal teas
Greece
no authorised or marketed products containing
Filipendula
, neither as single active
ingredient, nor in combination products
Hungary
Herb: only in combinations in “healing products”, a.o. herbal tea and gel for topical use
Latvia
no authorised or registered medicinal products containing
Filipendula
. However, several
food supplements containing
Filipendula
on the market
Netherlands no products containing
Filipendula
on the market
Slovak
republic
no products authorised
,
neither as a single active ingredient nor as combination
products
Slovenia
no authorised/registered medicinal product containing Filipendulae ulmariae flos
and
Filipendulae ulmariae
herba.
Spain
Herb: powdered herbal substance of dry flowering tops, hard
capsules 250 mg
MA 1993
Also available in combination products (herbal teas)
- (?)
Sweden
no products containing
Filipendula
on the market
Assessment report on
Filipendula ulmaria
(L.) Maxim. (=
Spiraea ulmaria
(L.)), herba
and
Filipendula ulmaria
(L.) Maxim. (=
Spiraea ulmaria
(L.)), flos
EMA/HMPC/434892/2010
Page 5/17
Regulatory status overview
H = herb
F = flowers
Member State Regulatory Status
Comments (not
mandatory field)
Austria
MA
TRAD
Other TRAD
Other Specify: No medicinal product on
market
Belgium
MA
TRAD
Other TRAD
Other Specify:
Bulgaria
MA
TRAD
Other TRAD
Other Specify: No products with MA on
market
Cyprus
MA
TRAD
Other TRAD
Other Specify:
Czech Republic
MA
TRAD
Other TRAD
Other Specify:
as food
supplement
H: only in combination
products, a.o. herbal tea
F: No products on
market
Denmark
MA
TRAD
Other TRAD
Other Specify: No products with MA on
market
Estonia
MA
TRAD
Other TRAD
Other Specify: No medicinal products
on market
Finland
MA
TRAD
Other TRAD
Other Specify:
France
MA
TRAD
Other TRAD
Other Specify: H: trad.: products with
MA on market; also in
combination products as.
herbal tea
F: trad.: products
without MA
Germany
MA
TRAD
Other TRAD
Other Specify: F: WEU (German
Standard MA): single
and in combination
products (all herbal
teas)
H: No products on
market
Greece
MA
TRAD
Other TRAD
Other Specify: No products on market
Hungary
MA
TRAD
Other TRAD
Other Specify: H: only in combinations
in “healing products”,
a.o. herbal tea and gel
for topical use
Iceland
MA
TRAD
Other TRAD
Other Specify:
Ireland
MA
TRAD
Other TRAD
Other Specify:
Italy
MA
TRAD
Other TRAD
Other Specify:
Latvia
MA
TRAD
Other TRAD
Other Specify: No products with MA on
Assessment report on
Filipendula ulmaria
(L.) Maxim. (=
Spiraea ulmaria
(L.)), herba
and
Filipendula ulmaria
(L.) Maxim. (=
Spiraea ulmaria
(L.)), flos
EMA/HMPC/434892/2010
Page 6/17
Member State Regulatory Status
Comments (not
mandatory field)
as food
supplement
market
Liechtenstein
MA
TRAD
Other TRAD
Other Specify:
Lithuania
MA
TRAD
Other TRAD
Other Specify:
Luxemburg
MA
TRAD
Other TRAD
Other Specify:
Malta
MA
TRAD
Other TRAD
Other Specify:
The Netherlands
MA
TRAD
Other TRAD
Other Specify: No products on market
Norway
MA
TRAD
Other TRAD
Other Specify:
Poland
MA
TRAD
Other TRAD
Other Specify:
Portugal
MA
TRAD
Other TRAD
Other Specify:
Romania
MA
TRAD
Other TRAD
Other Specify:
Slovak Republic
MA
TRAD
Other TRAD
Other Specify: No products with MA on
market
Slovenia
MA
TRAD
Other TRAD
Other Specify: No products with MA on
market
Spain
MA
TRAD
Other TRAD
Other Specify: H: single and in
combination products
(herbal teas)
Sweden
MA
TRAD
Other TRAD
Other Specify: No products on market
United Kingdom
MA
TRAD
Other TRAD
Other Specify:
MA: Marketing Authorisation
TRAD: Traditional Use Registration
Other TRAD: Other national Traditional systems of registration
Other: If known, it should be specified or otherwise add ’Not Known’
This regulatory overview is not legally binding and does not necessarily reflect the legal status of the
products in the MSs concerned.
1.3.
Search and assessment methodology
Databases assessed (date, search terms) and other sources used: to be completed.
2.
Historical data on medicinal use
2.1.
Information on period of medicinal use in the Community
The medicinal use of
Filipendula ulmaria
has been described from the late 16
th
and 17
th
century
(Halkes, 1998). In general, preparations form herb and/or flowers have been used traditionally in
inflammatory diseases (Madaus, 1938; Gessner and Orzechowski, 1974; Van Hellemont, 1988; Wichtl,
1994; Zeylstra, 1998; Halkes, 1998) and as a diuretic (Madaus, 1938; Gessner and Orzechowski,
1974; Van Hellemont, 1988; Wichtl, 1994; Zeylstra, 1998; Halkes, 1998). Zeylstra (1998) concludes
that the uses of
Filipendula
shifted over the years from a diuretic towards an antirheumatic.
In most literature herbal tea preparations are described, however Van Hellemont (1988) also mentions
a tincture. A product containing 250 mg of dried, powdered flowering tops in hard capsules which has
Assessment report on
Filipendula ulmaria
(L.) Maxim. (=
Spiraea ulmaria
(L.)), herba
and
Filipendula ulmaria
(L.) Maxim. (=
Spiraea ulmaria
(L.)), flos
EMA/HMPC/434892/2010
Page 7/17
been authorised in France in 1988 as a traditionally used medicine in the symptomatic treatment of
minor painful articular conditions and to facilitate renal and digestive elimination functions, has been
on the market since 1980 and was already mentioned in a price list dated January 1981 of the French
firm Laboratoires Arkochim. Dry aqueous extracts of the herb in capsules containing 200 mg
(indications: “traditionally used as an analgesic (headache, toothache)” and “traditionally used in the
symptomatic treatment of minor painful articular conditions”) have been marketed since 1986. Sachets
containing 1.5 g of fragmented herb have been marketed since 1990 as a traditionally used medicine
in the symptomatic treatment of minor painful joint conditions.
Assessor’s comment:
Conclusion: Only for the comminuted herbal substance for tea preparation and the powdered herbal
substance a period of at least 30 years of medical use as requested by Directive 2004/24/EC for
qualification as a traditional herbal medicinal product can be considered fulfilled. With respect to dry
and liquid extracts and tinctures older information is limited, sufficient details on extraction solvent and
drug-extract ratio are only available from 1983.
2.2.
Information on traditional/current indications and specified
substances/preparations
Whereas in the British Herbal Pharmacopoea (1983) stomachic, mild urinary antiseptic, antirheumatic
and antacid actions are listed, the British Herbal Pharmacopoeia (1990) and British Herbal
Compendium (1992) describe the action of Filipendula herba as anti-inflammatory. In addition, BHC
mentions diuretic, stomachic and astringent actions. As indications BHC (1992) describes “Atonic and
acid dyspepsia, gastritis and peptic ulceration”, as other uses “Rheumatic and arthritic pains (internally
and topically). In Belgium, according to regulatory guidelines, the indication must be stated as:
“Traditionally used for painful articular conditions although its activity has not been proved in
accordance with current evaluation criteria for medicines”, whereas in France the following therapetic
actions have been accepted: Oral use: “Traditionally used to facilitate renal and digestive elimination
functions, for febrile and influenzal conditions, as an antalgesic (headache, toothache), in the
symptomatic treatment of minor painful articular comditions and to promote the renal elimination of
water”. Topical use: “Traditionally used in the symptomatic treatment of minor painful articular
conditions” (BHC, 1992). The German Commision E monograph (Blumenthal, 1998) mentions the use
of both herb and flowers as supportive therapy for colds. ESCOP Monographs: Herb is used as
supportive therapy for the common cold and to enhance the renal elimination of water.
Diaphoretic, colds, flu and chills
reference
indication
preparation
Van Hellemont, 1988
H: diaphoretic, in flu and colds
F: diaphoretic, in flu and colds
H: infusion, tincture
F: infusion
British Herbal
Pharmacopoeia, 1990
H: Anti-inflammatory
Wichtl, 1994
F: diaphoretic for colds, chills etc.
F: infusion
Halkes, 1998
F: diaphoretic, as an additional
treatments for colds
F: aqueous decoctions and
infusions, alcoholic extracts
Blumenthal, 1998
H, F: supportive therapy for colds
H, F: comminuted herb and
other galenical preparations for
infusions
Zeylstra, 1998
F: diaphoretic
H: infusion, liquid extract,
tinctures
Assessment report on
Filipendula ulmaria
(L.) Maxim. (=
Spiraea ulmaria
(L.)), herba
and
Filipendula ulmaria
(L.) Maxim. (=
Spiraea ulmaria
(L.)), flos
EMA/HMPC/434892/2010
Page 8/17
Schulz et al., 1998
F: supportive therapy of colds
F: infusion
ESCOP, 2003
H: supportive therapy for colds
H: infusion, liquid extract,
tincture
Antirheumatic, anti-arthritic, analgesic, in diseases of muscles and joints
reference
indication
preparation
British Herbal
Pharmacopoeia, 1983
H: rheumatic muscle and joint pains H: infusion, liquid extract (1:1
in 25% alcohol), tincture (1:5 in
45% alcohol)
Van Hellemont, 1988
H: antirheumatic, in diseases of
muscle and joints
F: gout and rheumatic diseases
H: infusion, tincture
F: infusion, also for topical use
British Herbal
Pharmacopoeia, 1990
H: Anti-inflammatory
British Herbal Compendium,
1992
H: rheumatic and arthritic pains
H: dried herb or infusion, liquid
extract (1:1 in 25% alcohol),
tincture (1:5 in 45% alcohol)
Also for topical use
Wichtl, 1994
F: against rheumatism of muscles
and joints and against arthritis
F: infusion
Zeylstra, 1998
H: rheumatoid arthritis,
osteoarthritis, gouty conditions,
muscular rheumatism, lumbago,
sciatica
H: infusion, liquid extract,
tinctures
Barnes et al., 2007
H: Antirheumatic, rheumatic muscle
and joint pains
H: infusion, liquid extract (1:1
in 25% alcohol), tincture (1:5 in
45% alcohol)
Renal elimination function
reference
indication
preparation
Van Hellemont, 1988
H: diuretic
F: diuretic
H: infusion, tincture
F: infusion
Wichtl, 1994
F: diuretic
F: infusion
Zeylstra, 1998
H: diuretic, against albuminuria and
oliguria, uricosuric, stimulates
excretion of urea
H: infusion, liquid extract,
tinctures
ESCOP, 2003
H: to enhance the renal elimination of
water
H: infusion, liquid extract,
tincture
Others
reference
indication
preparation
British Herbal
Pharmacopoeia, 1983
H: atonic dyspepsia with heartburn
and hyperacidity, acute catarrhal
cystitis, prophylaxis and treatment of
peptic ulcer, diarrhoea in children
H: infusion, liquid extract (1:1
in 25% alcohol), tincture (1:5
in 45% alcohol)
Van Hellemont, 1988
H: antispasmodic, cholagogum.
F: in cystitis, pyelitis, nephritis,
H: infusion, tincture
Assessment report on
Filipendula ulmaria
(L.) Maxim. (=
Spiraea ulmaria
(L.)), herba
and
Filipendula ulmaria
(L.) Maxim. (=
Spiraea ulmaria
(L.)), flos
EMA/HMPC/434892/2010
Page 9/17
astringent, woundhealing, in
adipositas, cellulitis
British Herbal Compendium,
1992
H: atonic and acid dyspepsia,
gastritis and peptic ulceration
H: dried herb or infusion, liquid
extract (1:1 in 25% alcohol),
tincture (1:5 in 45% alcohol)
Zeylstra, 1998
H: antiseptic (cystitis, pyelites,
nephritis), against scarlet fever..
F: antacid, treatment of peptic ulcers,
gastritis
H: infusion, liquid extract,
tinctures
Barnes et al., 2007
H: stomachic, mild urinary antiseptic,
astringent, antacid, atonic dyspepsia
with heartburn and hyperacidity,
acute catarrhal cystitis, prophylaxis
and treatment of peptic ulcer,
diarrhoea in children
H: infusion, liquid extract (1:1
in 25% alcohol), tincture (1:5
in 45% alcohol)
Currently, the following specified products based on
Filipendula ulmaria
have been reported to be on
the market in the European Member States (indication numbers between brackets):
Herb: hard capsules for oral use containing 250–300 mg of powdered herbal substance (1, 2, 3), hard
capsules for oral use containing 169–200 mg of dry aqueous extract (s) (2, 3, 4) and sachets
containing 1.5 g of comminuted herbal substance for tea preparation (2).
Flowers: hard capsules for oral use containing 50 mg of dry ethanolic extract (3).
Indications mentioned:
1.
relief of symptoms of common cold
2.
relief of minor articular pain, traditionally used in the symptomatic treatment of minor painful
articular conditions
3.
traditionally used to facilitate renal and digestive elimination functions
4.
traditionally used as an analgesic (headache, toothache)
2.3.
Specified strength/posology/route of administration/duration of use
for relevant preparations and indications
Indication numbers 1-4 refer to 2.2 under Indications mentioned:
p.c. = personal communication
n.m. = not mentioned
Herb:
A1) Comminuted herbal substance (for tea preparation)
reference
single dose daily dose
indication
France, p.c.
1.5 g
3 – 4.5 g
2
BHP, 1983;
Barnes et al., 2007
4-6 g
12-18 g
2
Comm. E, 1998
n.m.
4-5 g
1
BHC, 1992
2-6 g
2-18 g
2
Assessment report on
Filipendula ulmaria
(L.) Maxim. (=
Spiraea ulmaria
(L.)), herba
and
Filipendula ulmaria
(L.) Maxim. (=
Spiraea ulmaria
(L.)), flos
EMA/HMPC/434892/2010
Page 10/17
ESCOP, 2003
n.m.
Adults: 2-6 g
Children 1-4 years: 1-2 g
Children 4-10 years: 2-3 g
Children 10-16 years: 2-6 g
1, 3
A2) Powdered herbal substance
reference
single dose daily dose
Indication
Spain, p.c.
250-500 mg 250-1500 mg
1, 2
France, p.c.
300 mg
900-1500 mg
2, 3
B1) Dry extract (DER?), water
reference
single dose daily dose
Indication
France, p.c.
200 mg
400 mg
2, 4
B2) Dry extract (DER?), water
reference
single dose daily dose
Indication
France, p.c.
169-507 mg 169-507 mg
2, 3
B3) Liquid extract (1:1; ethanol 25% v/v)
reference
single dose daily dose
indication
BHP, 1983;
Barnes et al., 2007
1.5-6.0 ml
4,5-18,0 ml
2
BHC, 1992
2-6 ml
2-18 ml
C) Tincture (1:5; ethanol 45% v/v)
reference
single dose daily dose
indication
BHP, 1983;
Barnes et al., 2007
2-4 ml
6-12 ml
2
BHC, 1992
2-4 ml
2-12 ml
Flowers:
A1) (Comminuted) herbal substance (for tea preparation)
reference
single dose daily dose
indication
Comm. E, 1998
n.m.
2.5-3.5 g
1
Wichtl, 1994
n.m. 3-6 g
1, 2, 3
Czech Republic,
p.c.
3.0 g
n.m.
n.m.
B) Dry extract (DER?), ethanol ? % (v/v)
reference
single dose daily dose
indication
France, p.c.
100-150 mg 200-450 mg
3
Assessor’s comment:
Since the information on the use of
Filipendula ulmaria
in and dosages for children is limited to only
one reference (herb; ESCOP, 2003, original reference: Dorsch et al., 1998) or completely lacking
Assessment report on
Filipendula ulmaria
(L.) Maxim. (=
Spiraea ulmaria
(L.)), herba
and
Filipendula ulmaria
(L.) Maxim. (=
Spiraea ulmaria
(L.)), flos
EMA/HMPC/434892/2010
Page 11/17
(flowers), and no exposure data in children are available, it is proposed not to include dosages for
children in the respective monographs.
No restriction on the duration of use has been mentioned for Filipendulae ulmariae herba or flos or
their preparations. However, since data on prolonged use are lacking the products should not be used
for more then ten days to four weeks, depending on the indication. Moreover the remark should be
added that if the symptoms persist during the use of these medicinal products, a doctor or a qualified
health care practitioner should be consulted.
3.
Non-Clinical Data
3.1.
Overview of available pharmacological data regarding the herbal
substance(s), herbal preparation(s) and relevant constituents thereof
Anti-inflammatory and antipyretic activity and related effects; effects on gastric ulcers
An aqueous leaf extract was reported to inhibit both prostaglandin biosynthesis and platelet activation
factor (PAF)-induced exocytosis/release of elastase (Tunon et al., 1995). The elastase inhibiting
properties of 50% (v/v) ethanolic flower and leaf extracts were attributed to the presence of tannins
(Lamaison et al., 1990).
Methanolic flower extracts (with flavonoids as main constituents) were demonstrated to strongly inhibit
xanthine oxidase activity
in vitro
(Kazazi et al., 2009).
Preparations of Filipendulae ulmariae flos have been reported to cause lowering of motor activity and
rectal temperature, myorelaxation and potentiation of narcotic action (Barnaulov et al., 1977), to
prolong life expectancy of mice, lower vascular permeability and prevent the development of stomach
ulcers in rats and mice (Barnaulov et al., 1977; Halkes, 1998).
Antiulcerative effects were also documented for other parts of the plant (Halkes, 1998; Barnes, 2007).
On the other hand, a flower decoction appeared to potentiate the ulcerogenic properties of histamine in
guinea-pigs. The greatest anti-ulcer activity is associated with aqueous flower extracts (Halkes, 1998;
Barnes et al., 2007). Orally administered flavonoids, as well as flower extracts from
Filipendula
ulmaria,
appeared to have a protective effect against reserpine-induced lesions of the rat stomach
(Halkes, 1998).
Immunomodulatory activity
Different extracts of both herb and flowers were shown to strongly inhibit luminol-dependent
chemiluminescence, T-cell proliferation and the classical pathway of the complement system, the latter
activity appearing to be not attributable to tannins (Halkes et al., 1997a). From a range of flower
extracts, prepared with different solvents, the ethyl acetate extract was found to exert the strongest
inhibition towards the classical pathway of complement activation, the active compound (s) however
being not identified (Halkes et al., 1997b). A flower decoction has been documented to enhance the
growth-stimulating activity of mice peritoneal macrophages, both
in vitro
and
in vivo
(Bespalov et al.,
1992).
Antibacterial activity
In vitro
bacteriostatic activity of several 70% ethanolic and aqueous flower extracts against a range of
urinary tract pathogens (Halkes, 1998; ESCOP, 2003; Barnes et al., 2007) have been described.
Growth-inhibitory effects (in vitro) against a variety of bacteria were also demonstrated for a
combination of 70% ethanolic and aqueous extracts (Csedõ et al., 1993).
Assessment report on
Filipendula ulmaria
(L.) Maxim. (=
Spiraea ulmaria
(L.)), herba
and
Filipendula ulmaria
(L.) Maxim. (=
Spiraea ulmaria
(L.)), flos
EMA/HMPC/434892/2010
Page 12/17
Anticarcinogenic activity
Flower decoctions have been reported to show anticarcinogenic activity against chemically induced
tumours in rats and mice (Bespalov et al., 1992; Halkes, 1998) and against transplanted tumours in
mice (Bespalov et al., 1992). Isolated rugosin D displayed antitumour activity against transplanted
tumours in mice (Miyamoto et al., 1987).
Other effects
An increase of bronchial tone in cats and a potentiation of bronchospastic properties of histamine in
guinea-pigs by ethanolic and aqueous preparations of Filipendulae ulmariae flos have been observed
(ESCOP, 2003; Barnes et al., 2007). Furthermore,
in vitro
enhancement of intestinal tone in guinea-
pigs and of uterine tone in rabbits (Barnes et al., 2007) has been described.
A heparin-like complex from the flowers showed
in vivo
anticoagulant and fibrinolytic properties in
animals after IM and IV injection (Kudriashov et al., 1990; Kudriashov et al., 1991).
Isolated rugosin D has been demonstrated to possess a high capacity for binding to bovine serum
albumine (BSA)
in vitro
(Beart et al., 1985; ESCOP, 2003).
3.1.1.
Overall conclusion on pharmacology:
Assessor’s comment:
In general, there seems to be no clear distinction between the pharmacological effects of (preparations
of) Filipendulae ulmariae herba (= flowering tops) and
Filipendulae ulmariae
flos. Also the Commission
E monograph describes the same use for both herbal substances, with only a different daily dosage:
2.5–3.5 g of flowers is considered equivalent with 4–5 g of herb.
Results from
in vitro
and
animal studies suggest anti-inflammatory/immunomodulatory, antibacterial
and anticarcinogenic activities.
In vivo
effects on the CNS in various animals include a.o. a reduction of
rectal temperature. The effects on gastric ulcers seem contradictory. No effects on renal and digestive
elimination functions have been reported.
3.2.
Overview of available pharmacokinetic data regarding the herbal
substance(s), herbal preparation(s) and relevant constituents thereof
No data with regard to absorption, distribution, metabolism, elimination or pharmacokinetic
interactions with other medicinal products are available.
3.3.
Overview of available toxicological data regarding the herbal
substance(s)/herbal preparation(s) and constituents thereof
Intraperitoneal LD
50
in mice and intravenous LD
50
in rabbits have been detemined as 1770 mg/kg and
75.7 mg/kg, respectively for an ethanolic flower extract (Barnaulov et al., 1977). For a flower
decoction (1:20) the intraperitoneal LD
50
in male and female mice and the intravenous LD
50
in rabbits
were determined as 535 mg/kg, 1050 mg/kg and 141.5 mg/kg respectively (ESCOP, 2003).
No influence on liver function of flowers and aqueous and ethanolic flower extracts could be observed
in pharmacological studies in rats and rabbits (Barnaulov et al., 1977; Halkes, 1998; ESCOP, 2003).
3.3.1.
Overall conclusion on toxicological data
Assessor’s comment:
There are only limited preclinical safety data for preparations of Filipendulae ulmariae herba or flos. In
view of the lack of data on mutagenicity, carcinogenicity and reproductive and developmental toxicity,
Assessment report on
Filipendula ulmaria
(L.) Maxim. (=
Spiraea ulmaria
(L.)), herba
and
Filipendula ulmaria
(L.) Maxim. (=
Spiraea ulmaria
(L.)), flos
EMA/HMPC/434892/2010
Page 13/17
a list entry for Filipendulae ulmariae herba or flos can not be recommended. In addition, the use during
pregnancy and lactation should be avoided.
Due to the presence of salicylates,
Filipendula ulmaria
should not be used in cases of hypersensitivity
to salicylates (Meier and Meier-Liebi, 1993; Wichtl, 1994).
3.4.
Overall conclusions on non-clinical data
Assessor’s comment:
Powdered meadowsweet herb as well as comminuted herb and chopped flowers for preparation of
herbal tea are used therapeutically in (commercially available) preparations in Europe for relief of
minor articular pain, supportive treatment of symptoms of common cold and to facilitate renal and
digestive elimination functions.
In general, there seems to be no clear distinction between the pharmacological effects of (preparations
of) Filipendulae ulmariae herba (= flowering tops) and Filipendulae ulmariae flos.
From
in vitro
and animal studies anti-inflammatory/immunomodulatory and anticarcinogenic activities
could be documented. In addition, antibacterial activity of flower extracts against a large number of
microorganisms was shown
in vitro
.
In vivo
effects on the CNS in various animals include a.o. a reduction of rectal temperature. This
antipyretic activity, together with the anti-inflammatory/immunomodulatory and antibacterial effects,
supports the use of the specified herbal preparations in the context of inflammatory diseases such as
painful articular conditions and common colds.
The effects on gastric ulcers seem contradictory. No effects on renal and digestive elimination functions
have been reported.
4.
Clinical Data
4.1.
Clinical Pharmacology
4.1.1.
Overview of pharmacodynamic data regarding the herbal
substance(s)/preparation(s) including data on relevant constituents
No data available.
4.1.2.
Overview of pharmacokinetic data regarding the herbal
substance(s)/preparation(s) including data on relevant constituents
No data available.
4.2.
Clinical Efficacy
4.2.1.
Dose response studies
No data available.
4.2.2.
Clinical studies (case studies and clinical trials)
Effect on cervical mucosa
Assessment report on
Filipendula ulmaria
(L.) Maxim. (=
Spiraea ulmaria
(L.)), herba
and
Filipendula ulmaria
(L.) Maxim. (=
Spiraea ulmaria
(L.)), flos
EMA/HMPC/434892/2010
Page 14/17
Local application of an ointment containing a flower decoction resulted in an improvement of cervical
dysplasia in 32 of 48 patients (67%), including 25 cases (52%) of complete regression. Within 10
months, no recurrence was observed in 10 completely cured patients (Halkes, 1998; ESCOP, 2003).
4.2.3.
Clinical studies in special populations (e.g. elderly and children)
No data available.
4.3.
Overall conclusions on clinical pharmacology and efficacy
Assessor’s comment:
Clinical data are limited to the study of the use of a flower decoction in cervical dysplasia as described.
Available data are considered insufficient to evaluate quality and design of the study. On this basis,
assessment of the efficacy in accordance with current guidance is not feasible.
No clinical data are available to contribute to the plausibility of efficacy for the specific indications of
Filipendulae ulmariae herba and flos in the context of inflammatory diseases such as painful articular
conditions and common colds.
5.
Clinical Safety/Pharmacovigilance
5.1.
Overview of toxicological/safety data from clinical trials in humans
No specific data available.
The Council of Europe categorizes Filipendulae ulmariae herba as a natural source of food flavouring
that can be added to foodstuffs in small quantities, with a possible limitation of an active principle (as
yet unspecified) in the final product (Barnes et al., 2007). According to the Botanical Safety Handbook
Filipendulae ulmariae herba is an herb that can be safely consumed when used appropriately
(McGuffin, 1997).
5.2.
Patient exposure
No clinical human data is available.
So far, no pharmacovigilance actions have been reported by any of the responding Member States
(based on information received from 15 MS, situation on 15-07-2010).
5.3.
Adverse events and serious adverse events and deaths
No data available.
5.4.
Laboratory findings
No data available.
5.5.
Safety in special populations and situations
No specific data is available on drug interactions, use in pregnancy and lactation, overdose, drug
abuse, withdrawal and rebound, effects on ability to drive or operate machinery or impairment of
mental ability. However, as safety during pregnancy and lactation has not been established, the use of
Filipendula ulmaria
during pregnancy and lactation should be avoided.
Assessment report on
Filipendula ulmaria
(L.) Maxim. (=
Spiraea ulmaria
(L.)), herba
and
Filipendula ulmaria
(L.) Maxim. (=
Spiraea ulmaria
(L.)), flos
EMA/HMPC/434892/2010
Page 15/17
Due to the presence of salicylates,
Filipendula ulmaria
should not be used in cases of hypersensitivity
to salicylates.
5.6.
Overall conclusions on clinical safety
Pregnancy and lactation:
As safety during pregnancy and lactation has not been established, the use during pregnancy and
lactation should be avoided.
Use in children:
Data on
Filipendula ulmaria
are scarce. Use in children and adolescents under 18 years of age is not
recommended because data are not sufficient and medical advice should be sought.
Drug interactions adverse effects and contra-indications:
No drug interactions are documented clinically. Theoretically, as preparations of
Filipendula ulmaria
may contain salicylates there might be a potential for interactions with other salicylate containing
products or other NSAID medicines administered concurrently. However, the amount of salicylates,
mostly present in the form of glycosides, is assumed to be less than 0.5 % (Zeylstra, 1998; ESCOP,
2003). According to Schulz et al. (1998) infusions contain only trace amounts of salicylates, so
meadowsweet tea is considered an aromatic remedy rather than a salicylate medication. Indeed, there
appears to be some doubt whether salicylates will play an important role in experimental or clinical
effects (Steinegger and Casparis, 1945; Halkes, 1998). With respect to adverse effects and contra-
indications, for willow bark (containing 0.5-10% of salicylates) (HMPC, 2009) it was concluded that
“there is no evidence that the types of reactions known to be associated with the pharmaceutical
salicylates is observed with Salix” (McGuffin, 1997). In addition, according to Wichtl (1994) “salicylate
side effects are not to be expected with the amount of salicylate derived from the drug (2-3 g of willow
bark) administered” and “there should be no increased interaction with blood coagulants”. Hence, for
(preparations of)
Filipendula ulmaria
, containing even less salicylates than
Salix, salicylates-related
interactions, adverse effects and contra-indications, can be considered unlikely. Nevertheless, although
side effects commonly associated with aspirin have not been observed with salicin-rich plants,
Filipendula ulmaria
should not be used in cases of hypersensitivity to salicylates.
Assessor’s comment:
Clinical safety data are very limited. On the other hand, no safety problems concerning the traditional
use of
Filipendula ulmaria
or its preparations have been reported. Although side effects, interactions
and contra-indications commonly associated with aspirin are considered unlikely,
Filipendula ulmaria
should not be used in cases of hypersensitivity to salicylates, In addition, the use during pregnancy
and lactation and in children and adolescents under 18 years of age is not recommended. In other
situations,
Filipendula ulmaria
preparations are considered not harmful when used in the recommended
dosages for the specified indications.
6.
Overall conclusions
In general, there seems to be no clear distinction between the pharmacological effects of (preparations
of) Filipendulae ulmariae herba (= flowering tops) and Filipendulae ulmariae
flos. Also the Commission
E monograph describes the same use for both herbal substances, with only a different daily dosage:
2.5–3.5 g of flowers is considered equivalent with 4–5 g of herb.
As no adequate clinical studies are available, preparations of neither Filipendulae ulmariae herba nor
Filipendulae ulmariae
flos can be qualified for well-established use indications.
Assessment report on
Filipendula ulmaria
(L.) Maxim. (=
Spiraea ulmaria
(L.)), herba
and
Filipendula ulmaria
(L.) Maxim. (=
Spiraea ulmaria
(L.)), flos
EMA/HMPC/434892/2010
Page 16/17
Since data on genotoxicity, mutagenicity and carcinogenicity studies are lacking, a list entry for neither
Filipendulae ulmariae herba nor Filipendulae ulmariae flos is considered to be applicable.
Also the amount of preclinical scientific data for
Filipendula ulmaria
preparations
appears to be limited.
From
in vitro
and
animal studies anti-inflammatory/immunomodulatory and anticarcinogenic activities
could be documented. In addition, antibacterial activity of flower extracts against a large number of
microorganisms was shown
in vitro
.
In vivo
effects on the CNS in various animals include a.o. a reduction of rectal temperature. This
antipyretic activity, together with the anti-inflammatory / immunomodulatory and antibacterial effects,
support the use of the specified herbal preparations in the context of inflammatory diseases such as
painful articular conditions and common colds. Their pharmacological effects or efficacy are considered
plausible on the basis of long-standing use and experience, as required by Art 16a 1 (e) of Directive
2004/24/EC.
For (comminuted) herbal substance (for tea preparation) in a daily adult dosage of 2-18 g (herb) or
2.5-6 g (flowers), respectively as well as for powdered herbal substance (herb) in a daily adult dosage
of 250-1500 mg, the period of traditional use as required by art. 16a 1 (d) and laid down in art. 16c 1
(c) of Directive 2004/24/EC is considered to be elapsed with respect to the following indications (for
both Filipendulae ulmariae flos
and
Filipendulae ulmariae herba, as well as their specified
preparations):
Traditional herbal medicinal product for the supportive treatment of common cold.
Traditional herbal medicinal product for the relief of minor articular pain.
The product is a traditional herbal medicinal product for use in the specified indication exclusively
based upon long-standing use.
These indications are considered as appropriate “…for use without the supervision of a medical
practitioner…” and subsequently to fulfil the requirements of art. 16a 1 (e) of Directive 2004/24/EC.
Recommended posology:
Herb:
(comminuted) herbal substance (for tea preparation): daily adult dosage of 2-18 g; single dose:
1.5-6 g
powdered herbal substance (herb): daily adult dosage 250-1500 mg; single dose: 250-500 mg
Flowers:
herbal substance (for tea preparation): daily adult dosage of 2.5-6 g; single dose: 2.5-3 g.
No experimental data is available on possible toxicity of (preparations of)
Filipendula ulmaria
.
However, in view of the results of the preclinical studies and the long period of marketing experience
without reports of adverse reactions, the specified
Filipendula ulmaria
herbal preparations can be
considered as proved not to be harmful in the specified conditions of use as required by Art. 16a 1 (e)
of Directive 2004/24/EC.
Annex
List of references
Assessment report on
Filipendula ulmaria
(L.) Maxim. (=
Spiraea ulmaria
(L.)), herba
and
Filipendula ulmaria
(L.) Maxim. (=
Spiraea ulmaria
(L.)), flos
EMA/HMPC/434892/2010
Page 17/17
Source: European Medicines Agency
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